A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer
We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non-small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance. Gene depletion, inhibitor treatment,...
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| Veröffentlicht in: | Clinical cancer research 2019-06, Vol.25 (12), p.3630-3642 |
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| creator | Zhang, Qianwen Zhang, Yan Chen, Yaqing Qian, Jianchang Zhang, Xuesai Yu, Ker |
| description | We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non-small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance.
Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine
and
efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelial-mesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape.
MTI-31 potently inhibited cell proliferation (IC |
| doi_str_mv | 10.1158/1078-0432.ccr-18-2548 |
| format | Article |
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Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine
and
efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelial-mesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape.
MTI-31 potently inhibited cell proliferation (IC
<1 μmol/L) and
tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met, or KRAS (MED <10 mg/kg). In EGFR-mutant and/or EML4-ALK-driven NSCLC, MTI-31 or disruption of mTORC2 reduced cell migration, hematogenous metastasis to the lung, and abrogated morphological and functional traits of EMT. Disruption of mTORC2 inhibited EGFR/T790M-positive tumor growth in mouse brain and prolonged animal survival correlating a diminished tumor angiogenesis and recruitment of IBA1+ microglia/macrophages in tumor microenvironment. MTI-31 also suppressed programmed death ligand 1 (PD-L1) in EGFR- and ALK-driven NSCLC, mediated in part by mTORC2/AKT/GSK3β-dependent proteasomal degradation. Depletion of mTOR protein or disruption of mTOR complexes profoundly downregulated PD-L1 and alleviated apoptosis in Jurkat T and primary human T cells in a tumor-T cell coculture system.
Our results highlight mTOR as a multifaceted regulator of tumor growth, metastasis, and immune-escape in EGFR/ALK-mutant and TKI-resistant NSCLC cells. The newly characterized mechanisms mediated by the rapamycin-resistant mTORC2 warrant clinical investigation of mTORC1/mTORC2 inhibitors in patients with lung cancer.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.ccr-18-2548</identifier><identifier>PMID: 30796032</identifier><language>eng</language><publisher>United States</publisher><ispartof>Clinical cancer research, 2019-06, Vol.25 (12), p.3630-3642</ispartof><rights>2019 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-981bbf214aad141cc156a950f4b167561ff24e5c8f38090196cf5c2e9cb12ff73</citedby><cites>FETCH-LOGICAL-c422t-981bbf214aad141cc156a950f4b167561ff24e5c8f38090196cf5c2e9cb12ff73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3357,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30796032$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Qianwen</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Chen, Yaqing</creatorcontrib><creatorcontrib>Qian, Jianchang</creatorcontrib><creatorcontrib>Zhang, Xuesai</creatorcontrib><creatorcontrib>Yu, Ker</creatorcontrib><title>A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non-small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance.
Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine
and
efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelial-mesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape.
MTI-31 potently inhibited cell proliferation (IC
<1 μmol/L) and
tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met, or KRAS (MED <10 mg/kg). In EGFR-mutant and/or EML4-ALK-driven NSCLC, MTI-31 or disruption of mTORC2 reduced cell migration, hematogenous metastasis to the lung, and abrogated morphological and functional traits of EMT. Disruption of mTORC2 inhibited EGFR/T790M-positive tumor growth in mouse brain and prolonged animal survival correlating a diminished tumor angiogenesis and recruitment of IBA1+ microglia/macrophages in tumor microenvironment. MTI-31 also suppressed programmed death ligand 1 (PD-L1) in EGFR- and ALK-driven NSCLC, mediated in part by mTORC2/AKT/GSK3β-dependent proteasomal degradation. Depletion of mTOR protein or disruption of mTOR complexes profoundly downregulated PD-L1 and alleviated apoptosis in Jurkat T and primary human T cells in a tumor-T cell coculture system.
Our results highlight mTOR as a multifaceted regulator of tumor growth, metastasis, and immune-escape in EGFR/ALK-mutant and TKI-resistant NSCLC cells. The newly characterized mechanisms mediated by the rapamycin-resistant mTORC2 warrant clinical investigation of mTORC1/mTORC2 inhibitors in patients with lung cancer.</description><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNo9kW9rFDEQxoMotlY_gpKXFS5tJrvZPy-PpdaFOytlfR2yucSLZLNnklXuS_kZzdmeMDDD8MwzM_wQeg_0BoA3t0DrhtCyYDdKBQINYbxsXqBL4LwmBav4y1yfNRfoTYw_KIUSaPkaXRS0bitasEv0Z42_zL-0w9Pw8NjBLcO939vRpjng6-3QkwI-nlsRD8uU-_dh_p32K3x3sGmvnZWObHXUXu2Pk3R4CNJHm-zsV3irk4w5dFxh6Xe4nw4hr4t47ZNN_9z6aVq8TUdsPf4atHLWW5VttvNOu4hngzeL_4476ZUOb9ErI13U757zFfr26W7oPpPNw33frTdElYwl0jYwjoZBKeUu_6wU8Eq2nJpyhKrmFRjDSs1VY4qGthTaShmumG7VCMyYurhC10---dyfi45JTDYq7Zz0el6iYNBwXtWsgCzlT1IV5hiDNuIQ7CTDUQAVJ1TihEGcMIiuexTQiBOqPPfhecUyTnr3f-rMpvgLmUeQYA</recordid><startdate>20190615</startdate><enddate>20190615</enddate><creator>Zhang, Qianwen</creator><creator>Zhang, Yan</creator><creator>Chen, Yaqing</creator><creator>Qian, Jianchang</creator><creator>Zhang, Xuesai</creator><creator>Yu, Ker</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20190615</creationdate><title>A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer</title><author>Zhang, Qianwen ; Zhang, Yan ; Chen, Yaqing ; Qian, Jianchang ; Zhang, Xuesai ; Yu, Ker</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-981bbf214aad141cc156a950f4b167561ff24e5c8f38090196cf5c2e9cb12ff73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Qianwen</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Chen, Yaqing</creatorcontrib><creatorcontrib>Qian, Jianchang</creatorcontrib><creatorcontrib>Zhang, Xuesai</creatorcontrib><creatorcontrib>Yu, Ker</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Qianwen</au><au>Zhang, Yan</au><au>Chen, Yaqing</au><au>Qian, Jianchang</au><au>Zhang, Xuesai</au><au>Yu, Ker</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2019-06-15</date><risdate>2019</risdate><volume>25</volume><issue>12</issue><spage>3630</spage><epage>3642</epage><pages>3630-3642</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non-small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance.
Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine
and
efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelial-mesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape.
MTI-31 potently inhibited cell proliferation (IC
<1 μmol/L) and
tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met, or KRAS (MED <10 mg/kg). In EGFR-mutant and/or EML4-ALK-driven NSCLC, MTI-31 or disruption of mTORC2 reduced cell migration, hematogenous metastasis to the lung, and abrogated morphological and functional traits of EMT. Disruption of mTORC2 inhibited EGFR/T790M-positive tumor growth in mouse brain and prolonged animal survival correlating a diminished tumor angiogenesis and recruitment of IBA1+ microglia/macrophages in tumor microenvironment. MTI-31 also suppressed programmed death ligand 1 (PD-L1) in EGFR- and ALK-driven NSCLC, mediated in part by mTORC2/AKT/GSK3β-dependent proteasomal degradation. Depletion of mTOR protein or disruption of mTOR complexes profoundly downregulated PD-L1 and alleviated apoptosis in Jurkat T and primary human T cells in a tumor-T cell coculture system.
Our results highlight mTOR as a multifaceted regulator of tumor growth, metastasis, and immune-escape in EGFR/ALK-mutant and TKI-resistant NSCLC cells. The newly characterized mechanisms mediated by the rapamycin-resistant mTORC2 warrant clinical investigation of mTORC1/mTORC2 inhibitors in patients with lung cancer.</abstract><cop>United States</cop><pmid>30796032</pmid><doi>10.1158/1078-0432.ccr-18-2548</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| title | A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer |
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